Cigna Nucleic Acid Pathogen Testing - (0530) Form

Medical Coverage Policy: 0530

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients.

Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based.

For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies.

In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document.

Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation.

Each coverage request should be reviewed on its own merits. Medical directors are expected to exercise clinical judgment where appropriate and have discretion in making individual coverage determinations.

Where coverage for care or services does not depend on specific circumstances, reimbursement will only be provided if a requested service(s) is submitted in accordance with the relevant criteria outlined in the applicable Coverage Policy, including covered diagnosis and/or procedure code(s).

Reimbursement is not allowed for services when billed for conditions or diagnoses that are not covered under this Coverage Policy (see “Coding Information” below). When billing, providers must use the most appropriate codes as of the effective date of the submission. Claims submitted for services that are not accompanied by covered code(s) under the applicable Coverage Policy will be denied as not covered.

Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines.

In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

This Coverage Policy discusses a type of lab test called nucleic acid infectious pathogen testing.

Bacteria, viruses, parasites and fungi, including yeast can cause infection. These are also known as pathogens. Nucleic acid testing works by finding parts of their gene material called DNA and RNA in the human body. Results of the tests can help decide how to treat the infection.

This Policy discusses testing for the DNA and/or RNA of several infection-causing bacteria, viruses and fungus that cause sexually transmitted diseases (STD). It can also find gene material of pathogens that can cause infections of the skin and nails, lungs, intestines, brain, kidneys, bladder and other parts of the body. When the test looks for more than one pathogen at the same time it is called panel testing.

This Policy does not discuss nucleic acid testing for SARS-CoV-2 (COVID-19) when the test only looks for this one virus. For that information, please see CP 0557 COVID-19: In Vitro Diagnostic Testing.

Testing performed in an inpatient level of care setting is not discussed in this Policy.

Medically Necessary

Nucleic acid pathogen testing for certain sexually transmitted infections (see CPT® code list below) is considered medically necessary for EITHER of the following:

• Asymptomatic individual with any of the following:
  • high-risk behavior (e.g., exposure to possible infected partner)
  • high-risk condition (e.g., pregnancy, HIV infection)
  • high-risk experience (e.g., assault)
  • chlamydia screening in sexually active individual
  • gonorrhea screening in sexually active individual
  • human papillomavirus (HPV) cervical cancer screening
• Symptomatic individual consistent with suspected diagnosis listed in the Coding Information section:

Pathogen

CPT® Codes

• Candida
• Chlamydia (Chlamydia trachomatis) 87490, 87491, 87492, 0353U
• 81513, 81514, 87510, 87511
• Gardnerella vaginalis 87528, 87529
• Herpes Simplex Virus (HSV) Types 1 and 2
• Gonorrhea (Neisseria gonorrhea)
• Human Papillomavirus (HPV), high-risk types (e.g., types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) 81514, 87480, 87481
• 87590, 87591, 0353U
• 87624

Medical Coverage Policy: 0530

Pathogen

CPT® Codes

• Trichomoniasis (Trichomonas vaginalis) 81514, 87660, 87661

Infectious pathogen detection by nucleic acid panel is considered medically necessary for the following:

• respiratory pathogens, not to exceed one test per date of service, up to 12 tests per 12 rolling months (i.e., up to 5 targets)
• gastrointestinal pathogens (i.e., up to 5 targets)
• central nervous system pathogens (i.e., 12-25 targets)

Not Covered or Reimbursable

Nucleic acid pathogen testing of single pathogen or by panel is not covered or reimbursable if performed in an outpatient level of care setting and the criteria described above are not met.

Nucleic acid pathogen testing is not covered or reimbursable for the diagnosis of ANY of the following indications if performed in an outpatient level of care setting (Please see Coding Information section):

• human papilloma virus (HPV), low-risk types (e.g., types 6, 11, 42, 43, 44)
• nail dystrophy
• skin and/or nail fungal infections (e.g., tinea, onychomycosis)
• infections of the urinary tract (i.e., pyelonephritis, cystitis, prostatitis)
• syphilis

Nucleic acid quantification to monitor for disease progression or therapy outcomes is not covered or reimbursable for the following pathogens:

• Gardnerella vaginalis
• non-invasive Candida
• Neisseria gonorrhea
• herpes simplex virus (HSV) Types 1 & 2

Use of Not Otherwise Specified (NOS) CPT codes: 87797, 87798, 87799, for molecular microbe testing is not covered or reimbursable when a more specific CPT/HCPCS code is available for use.

General Background

The purpose of infectious pathogen testing using nucleic acid laboratory methods is to identify the deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) of disease-causing microorganisms, including viruses, bacteria, parasites and fungi, including yeast, for the purpose of diagnosis and treatment. Nucleic acid pathogen testing provides sensitive, specific and timely identification of microorganisms. A nucleic acid test analyzes tiny amounts of DNA or RNA in a sample of blood, tissue or body fluid, sputum, stool, urine and cerebrospinal fluid. Because the amount of genetic material is very small the test may include a step where the DNA or RNA of the microorganism is amplified, or

increased. This type of nucleic acid pathogen test is known as a nucleic acid amplification test or NAAT. The NAAT format increases diagnostic sensitivity by decreasing the lower limit of detection.

Standard laboratory tests

Standard laboratory tests for the diagnosis of the skin, soft tissue, nails and mucosal tissues are fungal culture, calcofluor-KOH preparation stain, blood culture and histopathology (IDSA, 2018). Increasingly, nucleic acid testing is being used to establish a diagnosis of invasive candida (i.e., candidemia) and candidiasis (i.e., vaginal yeast infection). The role of nucleic acid pathogen testing to identify candida as a causative pathogen in the diagnosis of onychomycosis or nail dystrophy has not been established.

Chlamydia (Chlamydia Trachomatis)

Chlamydial infection is the most frequently reported infectious disease in the United States (IDSA, 2018; CDC, 2015). Individuals with chlamydia may be asymptomatic or symptomatic. If symptomatic, presenting symptoms include cystitis with or without hematuria, urethritis, acute vulvo-vaginitis, lower urogenital tract infection, pelvic inflammatory disease, acute prostatitis, proctitis, epididymitis, orchitis, cervicitis, endometritis, genital lesions, dysuria and urethral discharge. Chlamydial infections in women can lead to serious consequences including pelvic inflammatory disease, tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. Sexually acquired chlamydial conjunctivitis can occur in both males and females through contact with infected genital secretions. Chlamydia can also be spread from an untreated mother to her baby during childbirth, resulting in ophthalmia neonatorum (conjunctivitis) or pneumonia in some exposed infants (IDSA, 2018; CDC, 2015). A number of diagnostic tests for chlamydia are available, including cell culture and nucleic acid pathogen tests. Nucleic acid tests are the most sensitive tests and are recommended by the CDC. These tests can be performed on easily obtainable specimens such as vaginal swabs (either clinician- or patient-collected) or urine. Chlamydia can be diagnosed by testing first-catch urine in both males and females or collecting swab specimens from the endocervix or vagina in females or the urethra in males. Rectal and oropharyngeal chlamydial infection in persons engaging in receptive anal or oral intercourse can be diagnosed by testing at the anatomic site of exposure. Specimens can be collected by a healthcare provider or can be self-collected (IDSA, 2018; CDC, 2015).

Gardnerella Vaginalis (Bacterial Vaginosis)

Gardnerella vaginalis (Gardnerella) is also known as bacterial vaginosis. Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women of child-bearing age. It is characterized by an overgrowth of anaerobic bacteria. Presenting symptoms include cystitis with or without hematuria, urethritis, acute vaginitis and dysuria (CDC, 2015) The gram stain is the gold standard for diagnosis of bacterial vaginosis. Amsel's criteria (i.e., thin, white, homogeneous discharge; clue cells on microscopy of wet mount; pH of vaginal fluid greater than 4.5; and release of a fishy odor on adding alkali (10 % KOH)) is recommended if gram stain is not available. BV diagnosis is defined clinically by the presence of three of four of the Amsel’s criteria (IDSA, 2018; CDC, 2015).

Gonorrhea (Neisseria Gonorrhea)

Neisseria gonorrhea, also known as N. gonorrhea or gonorrhea infects the mucous membranes of the reproductive tract, including the cervix, uterus, and fallopian tubes in women, and the urethra in women and men. Gonorrhea can also infect the mucous membranes of the mouth, throat, eyes, and rectum. An individual with gonorrhea may be asymptomatic or symptomatic.

If symptomatic, presenting symptoms include pharyngitis, cystitis with or without hematuria, genital lesions, vulvo-vaginitis, endometritis, urethritis, cervicitis, dyspareunia, urethral discharge, prostatitis, epididymitis, orchitis and painful bowel movements. Pharyngeal infection may cause a sore throat.

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Other symptoms include spondylopathy, osteomyelitis, meningitis, brain abscess, pneumonia, peritonitis and gonococcal heart infection. Gonorrheal infection can be passed from a mother to her baby during delivery and may result in blindness, joint infection or sepsis (IDSA, 2018; CDC, 2015). Urogenital gonorrhea can be diagnosed by testing urine specimens for male and female, urethra specimens in males or endocervical or vaginal specimens in females. Nucleic acid tests are recommended by the CDC for this indication. If an individual has had oral and/or anal sex, pharyngeal and/or rectal swab specimens can also be collected (IDSA, 2018; CDC, 2015).

Herpes Simplex Virus Types 1 and 2

Genital herpes is caused by the herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). Infections are transmitted through contact with HSV in herpetic lesions, mucosal surfaces, genital secretions, or oral secretions. HSV-1 and HSV-2 can be shed from normal-appearing oral or genital mucosa or skin. Individuals may be asymptomatic or symptomatic. If symptomatic, presenting symptoms include small painful blisters, rash or skin eruption on or around the penis, scrotum, testes, anus, rectum, vagina, lips, mouth and oral cavity. Both HSV-1 and HSV-2 can also cause rare but serious complications such as aseptic meningitis (inflammation of the linings of the brain). Development of extragenital lesions (e.g. buttocks, groin, thigh, finger, or eye) may occur during the course of infection. Genital herpes may also cause painful genital ulcers that can be severe and persistent in persons with suppressed immune systems, such as HIV-infected persons and make it easier to transmit and acquire HIV infection sexually. Neonatal herpes is one of the most serious complications of genital herpes. Herpes infection can be passed from mother to baby during pregnancy or childbirth, or babies may be infected shortly after birth, resulting in a potentially fatal neonatal herpes infection (IDSA, 2018; CDC, 2015). Because viral shedding is intermittent, failure to detect HSV does not indicate an absence of HSV infection. A direct fluorescent antibody test, isolation by viral culture to detect herpes DNA in an individual with active herpes or nucleic acid pathogen test are recommended for diagnosis (ISDA, 2018; CDC, 2015).

Human Papillomavirus (HPV)

Some types of HPV can cause genital warts (e.g., low- risk types 6, 22, 42, 43, 44) while other types can cause cancer (e.g., high-risk (oncogenic) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). Genital warts usually appear as a small bump or group of bumps in the genital area of both men and women. The warts can be small or large, raised or flat, or shaped like a cauliflower (ACS, 2019). A healthcare provider can usually diagnose genital warts by looking at the genital area. Rarely, there is transmission of the virus from mother to baby during birth. When this does occur, a baby born to a woman who has genital warts may develop warts in the throat. The role of nucleic acid pathogen testing for the diagnosis of low-risk HPV has not been established. High-risk HPV can cause cancer of the cervix, vulva, vagina, penis, anus or in the back of the throat, including the base of the tongue and tonsils. To date there is no FDA-approved test for the screening or diagnosis of HPV in males (CDC, 2015; American Cancer Society [ACS], 2018).

DNA hybridization probe or nucleic acid testing is available to diagnosis high-risk HPV types in females (IDSA, 2018; CDC, 2015). This type of test can be used in combination with the Pap test or alone to test for cervical cancer and is recommended for a female ≥ 30 years of age. Nucleic acid pathogen testing can also be used in women who have slightly abnormal Pap test results (i.e., atypical squamous cells of undetermined significance [ASCUS]) to determine if additional testing or treatment is needed (ACS, 2018).

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Syphilis

Syphilis is caused by the bacterium Treponema pallidum. Standard testing methods include serologic treponemal and non-treponemal antibody testing, which are not included in the scope of this Coverage Policy. The role of nucleic acid pathogen testing for the screening or diagnosis of syphilis has not been established (CDC, 2015).

Trichomoniasis (Trichomonas vaginalis)

According to the CDC (2015), trichomoniasis is the most prevalent nonviral sexually transmitted disease in the United States. The parasite may pass from an infected person to an uninfected person during sexual intercourse. In females, the most commonly infected part of the body is the lower genital tract (vulva, vagina, cervix, or urethra); while in males the urethra is most often infected. It is not common for the parasite to infect other body parts, like the hands, mouth, or anus. Many individuals who have trichomonas are asymptomatic. If symptoms are present they may include urethral or vaginal discharge, cystitis, urethritis, endometritis, burning or redness of the genitals, itching or irritation inside the penis, epididymitis, prostatitis and burning after urination or ejaculation. Trichomonas vaginalis infection is associated with two- to threefold increased risk for HIV acquisition, preterm birth, and low birth weight (CDC, 2015). Culture was considered the gold standard method for diagnosing trichomonas infection before molecular detection methods, such as nucleic acid pathogen testing became available. Microscopic evaluation of wet preparations of genital secretions is relatively convenient and of low cost; although sensitivity is low in vaginal specimens and in urethral, urine sediment and semen in males. Among females, FDA-approved nucleic acid amplification tests (NAAT) are highly sensitive. Although not FDA-approved for use in males, nucleic acid pathogen tests can be used with urine or urethral swabs from men if validated per CLIA regulations (CDC, 2015). Other testing methods used less commonly include rapid antigen tests and DNA hybridization probes (IDSA, 2018).

Nucleic Acid Infectious Pathogen Panels

Detection of infectious pathogens using nucleic acid panels has been proposed as a quick and convenient method to detect multiple infectious pathogens using a single sample source. Available panel tests include those that identify disease-causing viruses, parasites and bacteria from blood, sera, plasma, stool, and nasopharyngeal aspirates. Other laboratory techniques used to diagnose infectious disease and respiratory, gastrointestinal and central nervous pathogens include serology, microscopy, immunofluorescence and culture. Selection of infectious pathogens for testing is based on subjective and objective assessment of an individual’s signs and symptoms. The clinical utility of panel testing for greater than five respiratory or gastrointestinal infectious pathogens in the outpatient setting has not been established in the published, peer-reviewed medical literature. An expanded nucleic acid panel test to detect up to 25 infectious pathogens related to the central nervous system may be considered clinically useful.

Nucleic Acid Quantification

Nucleic acid quantification is a molecular laboratory method performed to determine the average concentration of DNA or RNA in a sample. Quantitative (vs. qualitative) viral results may be useful for interpreting tests, particularly with regard to viruses causing latent infection or for monitoring therapy or disease progression. Interpretation of any result requires integration of the clinical history, laboratory data, treatment records, and observation of trends over time (Humphries and Miller, 2019). There is insufficient evidence in the published peer-reviewed literature to support nucleic acid quantification for the monitoring of disease progression or therapy outcomes for candida, gardnerella, gonorrhea or herpes simplex virus (HSV) Types 1 & 2. Published professional society recommendations regarding the use of nucleic acid quantification for these pathogens are also lacking.

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Tinea

Tinea represents a group of diseases caused by a fungus. Types of tinea include ringworm, athlete's foot and jock itch (Medline Plus, 2020). Published professional society guidelines do not support nucleic acid pathogen testing to diagnose tinea. According to the Infectious Disease Society of America (IDSA, 2018) laboratory procedures of value for the diagnosis of dermatophytes/tinea in skin and subcutaneous infection are fungal culture, calcofluor-KOH preparation and histopathology. The role of nucleic acid pathogen testing for the diagnosis of tinea has not been established.

Urinary Tract Infection

There is insufficient evidence to support the use of nucleic acid testing for the diagnosis of urinary tract infections, including pyelonephritis, cystitis, prostatitis and orchitis. Urinary tract infections are among the most common bacterial infections in women. Most urinary tract infections are acute uncomplicated cystitis. A urinalysis, but not urine culture, is recommended in making the diagnosis. Urine cultures are recommended in women with suspected pyelonephritis, women with symptoms that do not resolve or that recur within two to four weeks after completing treatment, and women who present with atypical symptoms (Colgan, 2011, CDC 2017). Regarding recurrent uncomplicated urinary tract infection in women, the American Urological Association (2019, reviewed and confirmed 2022) notes that clinicians must document positive urine cultures associated with prior symptomatic episodes. The Clinical Guideline also notes clinicians should obtain urinalysis, urine culture and sensitivity with each symptomatic acute cystitis episode prior to initiating treatment in patients with recurrent UTIs. The IDSA (2018) describes clinical microbiology tests of value in establishing an etiologic diagnosis of infections of the urinary tract, including laboratory procedures for the diagnosis of cystitis, pyelonephritis, prostatitis, epididymitis and orchitis. According to the IDSA, diagnosis of urinary tract infections requires clinical information and physical findings as well as laboratory information. Culture is noted to be appropriate test for the diagnosis of yeast in urine and acute bacterial prostatitis. Rarely, yeast in urine may rarely indicate systemic infection, for which additional tests must be conducted for confirmation (e.g., blood cultures and β-glucan levels). Detection of adenovirus in cases of cystitis is usually done by NAAT. Polyoma BK virus nephropathy is best diagnosed by quantitative molecular determination of circulating virus in blood rather than detection of virus in urine. Acute bacterial prostatitis is defined by clinical signs and physical findings combined with positive urine or prostate secretion cultures yielding usual urinary tract pathogens.

U.S. Food and Drug Administration (FDA)

Multiple nucleic acid-based infectious pathogen tests have been cleared or approved by the Center for Devices and Radiological Health for the detection of infectious pathogens. According to the FDA, these tests analyze variations in the sequence, structure, or expression of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in order to diagnose disease or medical conditions, infection with an identifiable pathogen, or determine genetic carrier status. Information regarding specific tests may be found on the FDA website at the following URL address: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm330711.htm

Professional Societies/Organizations

Centers for Disease Control and Prevention ([CDC]; 2015):

2015 Sexually Transmitted Diseases Treatment Guidelines note that nucleic acid pathogen testing is available for chlamydia, gonorrhea and trichomonas.

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Infectious Disease Society of America (IDSA)/American Society for Microbiology (ASM) (2018):

On behalf of the IDSA/ASM, Miller et al. published A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 update by the Infectious Diseases Society of America and the American Society for Microbiology. Regarding laboratory diagnosis of fungal infections of skin and subcutaneous tissue, specifically for dermatophytes/tineas and yeast like fungal infections, the IDSA notes fungal culture, calcofluor-KOH preparation and histopathology are valuable diagnostic procedures used for such infections. For other fungal infections, urine antigen, fungal serology and blood culture are noted as additional diagnostic procedures. The IDSA does not recommend nucleic acid testing as a laboratory method to diagnose fungal infections of the skin and subcutaneous tissue (2018).

Regarding infections of the urinary tract, specifically for the diagnosis of cystitis, pyelonephritis, prostatitis, epididymitis and orchitis, the IDSA notes that routine aerobic culture and gram stain are tests of value related to the diagnosis of pyelonephritis and cystitis. NAAT may be of value in diagnosing adenovirus and BK polyoma virus. Aerobic and fungal culture, mycobacterial culture and serology are tests of value for the diagnosis of various pathogens associated with prostatitis. NAAT and culture are valuable to diagnose Chlamydia trachomatis and Neisseria gonorrhoeae in the setting of epididymitis.

American Urological Association ([AUA], 2019):

Regarding uncomplicated urinary tract infections in women the AUA notes:

• To make a diagnosis of recurrent UTI, clinicians must document positive urine cultures associated with prior symptomatic episodes. (Clinical Principle)
• Clinicians should obtain urinalysis, urine culture and sensitivity with each symptomatic acute cystitis episode prior to initiating treatment in patients with recurrent UTIs. (Moderate Recommendation; Evidence Level: Grade C)
• Clinicians should omit surveillance urine testing, including urine culture, in asymptomatic patients with recurrent UTIs. (Moderate Recommendation; Evidence Level: Grade C)

(Grade C: Net benefit (or net harm) appears moderate. Applies to most patients in most circumstances but better evidence is likely to change confidence)

U.S. Preventive Services Task Force ([USPSTF], 2021):

The Task Force notes Nucleic acid amplification tests (NAATs) for Chlamydia trachomatis and Neisseria gonorrhoeae infections are usually used for screening because their sensitivity and specificity are high for detecting these infections.

There are a number of FDA approved tests for use on urogenital and extragenital sites, including urine, endocervical, vaginal, male urethral, rectal, and pharyngeal specimens. Urine testing with NAATs is at least as sensitive as testing with endocervical specimens, clinician- or self-collected vaginal specimens, or urethral specimens in clinical settings. The same specimen can be used to test for chlamydia and gonorrhea.